Susan Urba and Joseph A. Bovi

MANAGEMENT OF COMMON SYMPTOMS

Patients with lung cancer commonly present with symptoms from their cancer or its treatment. Sixty-five percent of patients with early stage cancer, and 74% of patients with late-stage cancer experience moderate-to-severe symptoms (1). The most common symptoms include cough, dyspnea, and pain. The medical oncologist is called upon to manage these problems, while simultaneously coordinating cancer-directed therapy.

Airway Symptoms

Cough

Cough is present in 47% to 86% of lung cancer patients (2). Tumor-related etiologies for cough include direct stimulation of the central airway mucosa by tumor, sputum accumulation, lymphangitic spread of disease, and pleural or pericardial effusion. Pneumonitis may occur in patients treated with localized radiation therapy (RT), and cough may result from this inflammatory response. Unrelenting cough is a major impediment to quality-of-life. The cough can annoy both patients and those around them to the point that they withdraw from social activities. It can interfere with sleep, preventing patients from falling asleep or staying asleep. This can exacerbate fatigue, which is already frequently a problem.

The underlying principle of therapy is to treat any reversible cause of the cough: chemotherapy or RT for the cancer, antimicrobials for infection, or thoracentesis for a pleural effusion. However, other measures can be used simultaneously to try to give the patient relief. There is a paucity of randomized clinical trial data comparing cough suppressants in patients with lung cancer. As a matter of fact, a meta-analysis of 17 trials assessing cough interventions concluded that no practice recommendations could be drawn from its review, and that there is an urgent need to increase the number and quality of studies evaluating the effects of interventions for the management of cough in cancer (3). Therefore, agents that have been developed as antitussives for the general population are most often used for patients with lung cancer.

Benzonatate: This is an oral, nonopiate, peripherally acting antitussive. It is dosed at 100 mg orally three times a day. There is evidence that when added to opiates, there may be additional improvement in cough suppression (4).

Dextromethorphan: A meta-analysis has been reported of six randomized, double-blind studies of single-dose dextromethorphan 30 mg versus placebo, utilizing a 3-hour postdose cough evaluation (5). It demonstrated significantly greater overall reductions in cough bouts, cough components, and cough effort, and an increase in cough latency for patients treated with dextromethorphan versus those treated with placebo.

Guaifenesin: Expectorants such as guaifenesin are used for patients who have thick mucus secretions, in order to allow thinning of the secretions so that the cough may be more productive, which may make the patient more comfortable. However, it does little to actually stop the coughing.

Opiates: Opiates are thought to act on µ-receptors in the central cough center, and they often become the mainstay of treatment for lung cancer patients with chronic cough. Codeine is the oldest cough suppressant and is often combined with other peripherally acting agents, such as dextromethorphan. A meta-analysis of 49 studies that included 3,067 patients reviewed opiate and nonopiate agents used for cough suppression (6). In studies that had an active or placebo comparison, codeine and dextromethorphan were found to reduce the frequency and severity of chronic cough. In 11 comparisons of opioids versus placebo, eight showed that opioids were more effective for decreasing cough frequency and severity and improving quality of life. Combination products are available that include both an opiate and another type of cough suppressant in one product, such as Robitussin AC (guaifenesin and codeine) and Tussionex (chlorpheniramine and hydrocodone).

Corticosteroids: Some patients have bronchospasm either from chronic obstructive pulmonary disease (COPD) or as part of the clinical scenario related to their lung cancer. For this group, dexamethasone 4 mg one to three times a day may be useful. Patients who develop radiation pneumonitis leading to a severe cough as the result of a relatively large radiation port may benefit from steroids. The data guiding dosing of steroids is very old, and mostly based on animal models. A typical approach would include prednisone 60-mg daily × 1 to 2 weeks, followed by a slow taper over several weeks (7).

Dyspnea

One of the most frightening symptoms that lung cancer patients may have to face is dyspnea. The crucial first step is to make a thorough evaluation of the cause. Some of the problems that cause cough are also responsible for dyspnea, including the tumor compressing or blocking a bronchus, pleural effusion, pneumonia, lymphangitic spread of cancer, radiation pneumonitis, or pulmonary embolism. Besides trying to relieve the cause of the dyspnea, there are several mainstays of symptomatic treatment that can also be implemented.

Oxygen: Many patients complain of shortness of breath, despite the fact that their oxygen saturation is greater than 90%. Unfortunately, most insurance companies will not pay for supplemental oxygen if the oxygen saturation is not in the 80s, even though some patients with a “normal” oxygen level do find some relief with supplemental oxygen.

Opiates: Opiate medications are a mainstay for the management of dyspnea. For patients who are opiate naïve, starting doses are similar to starting doses for pain management. Morphine would be started at 2.5 to 10 mg orally every 2 hours (8). Oxycodone would be started at 5 mg every 3 to 4 hours. For elderly patients, these doses should be even lower. If the patient is already on chronic opiates for pain control, consideration can be given to increasing the dose by 25%.

Nebulized morphine has been studied because of its potentially rapid onset of action and ease of administration, and because if less of the opiate is absorbed systemically, adverse reactions might be minimized. A systematic review of 18 randomized, double-blind, controlled trials of opiates (nine of these trials used nebulized opiates) for relief of dyspnea in terminally ill patients concluded that there was no evidence to support nebulized opiate administration. However, there was evidence to support the use of oral or intravenous opiates (9).

Benzodiazepines: Opiates may not be sufficient to relieve dyspnea in some patients. If there is a substantial anxiety component, then a benzodiazepine such as lorazepam 0.5 to 1 mg every 4 hours as needed is helpful. Elderly patients may not tolerate a benzodiazepine, because they may experience paradoxical agitation from it. In that case, gentle titration of the opiate may be preferable to the addition of a benzodiazepine.

Nonpharmacologic measures: Several changes can be made to the patient’s local environment to help relieve the sensation of dyspnea. Even though there is little randomized data to support these measures, anecdotally they may improve patient comfort. A bedside fan should be kept on, at a comfortable distance from the patient, to give the sensation of movement of cool air. The room should not be kept dark and close, but rather as airy as possible, with an open window or open door to reduce the sensation of “smothering.” The patient may need to sleep in a semi-upright position in a recliner chair or propped up in bed with several pillows.

Anxiety and stress related to dyspnea can aggravate breathlessness, so it is important to consider relaxation techniques or guided imagery as an adjunct to symptom management. Often, the family can be educated in a few simple techniques of relaxed deep breathing in order to help the patient at home in a time of crisis.

Radiation for Airway Symptoms

Symptoms that originate from advanced cancer within the thoracic cavity can be palliated with a number of therapeutic modalities, such as external beam RT, brachytherapy, chemotherapy, surgical procedures, and/or supportive care. In this section, we concentrate on the radiotherapeutic options (10).

External beam RT: Palliative RT continues to play a pivotal role in the management of thoracic symptoms from lung cancer. It is particularly beneficial for endobronchial or extrinsic lesions causing atelectasis, postobstructive pneumonia, shortness of breath, cough, hemoptysis, pain, and large airway obstruction. RT cannot be expected to relieve shortness of breath that results from other cancer-related causes such as widespread parenchymal tumor involvement, pleural effusion, or lymphangitic tumor dissemination. Careful evaluation of the source of the patient’s dyspnea must be paid attention to.

Numerous randomized trials have compared different palliative thoracic RT schedules for non–small-cell lung cancer (NSCLC). Many, but not all studies, have suggested that a less extensive course of RT consisting of 17 Gy (8.5 Gy × 2, delivered 1 week apart) or 10 Gy in a single fraction provide better palliation. In a Medical Research Council (MRC) study, shorter treatment regimens resulted in 80% to 85% of patients reporting an improvement in hemoptysis, 60% reporting an improvement in cough, and two-thirds reporting improvement in pain (11). An additional MRC study randomized 369 patients to 17 Gy (8.5 Gy × 2, delivered 1 week apart) versus 30 Gy in 10 fractions, with 81% of patients achieving improvement in hemoptysis with the short course of therapy compared to 86% in the longer treatment arm. These results were not statistically different from one another. Cough was improved in 65% of patients in the short course arm and in 56% of patients in the longer treatment arm, and again no statistical difference was detected. These results support the use of shorter treatment regimens in these patients (12). An additional study by Teo et al. randomized 291 patients to 45 Gy in 18 fractions over 4½ weeks versus 31.2 Gy in four fractions over 4 weeks (7.8 Gy once per week). There was better symptom palliation with the 18-fraction treatment regimen, (71% vs. 54%) (13). Finally, Simpson et al., in Radiation Therapy Oncology Group (RTOG) 73-02, published on 409 patients randomized to 40 Gy in 10 fractions over 5 weeks versus 40 Gy in 20 fractions over 4 weeks versus 30 Gy in 10 fractions over 2 weeks. This study did not show superiority of one-fractionation regimen over another in terms of symptom control, again suggesting that a shorter fractionation schedule is as effective as a more protracted treatment schedule (14).

The third in a series of MRC studies on NSCLC was intriguing in that it suggested that a higher RT dose, 39 Gy in 13 fractions, may result in prolonged survival in good performance status patients as compared to 17 Gy (8.5 Gy × 2, delivered 1 week apart) (15). Subsequent to this MRC trial, a Canadian randomized trial of 10 Gy in a single fraction versus 20 Gy in five fractions revealed a 2-month longer median survival in patients in the multifraction arm, 6 months with 20 Gy versus 4.2 months with 10 Gy (16). To date, no dose fractionation schedule has demonstrated clear superiority in terms of palliation.

It is unclear if external beam RT should be recommended in patients who have minimal or no thoracic symptoms. This was examined by an additional MRC study (17). In this randomized, controlled trial, 230 patients with previously untreated incurable NSCLC, but no symptoms that would require immediate thoracic RT were randomized to either immediate RT (8.5 Gy × 2, delivered 1 week apart or a single 10 Gy fraction) delivered to their thoracic primary tumor or delayed RT as required at the time of symptom occurrence. The primary endpoint was the proportion of patients alive and free of moderate or severe thoracic symptoms at 6 months. This proportion was also examined at 1, 2, and 4 months. At no point was there a difference observed between the two study arms, with 28% of patients in the immediate RT arm and 26% of patients in the delayed RT arm remaining alive and free of moderate or severe symptoms at 6 months. In the delayed RT arm, 42% of patients received subsequent RT to their thoracic primary tumor and 56% died without receiving RT. Survival was similar with immediate or delayed RT. This study suggests that in patients who are candidates for radical treatment, prophylactic palliative RT should not be routinely used.

Endobronchial brachytherapy: In patients who have already received a prior course of external beam RT or in cases where an endobronchial tumor is causing obstruction of a major airway, direct insertion of radioactive sources into the bronchial lumen may be considered. This is called endobronchial brachytherapy. The most commonly used source is iridium-192 delivered through a high dose-rate after-loading device. Reported response rates have varied between 70% and 90% in appropriately selected patients (18). Small tumors less than 2 cm in size may be effectively palliated for long periods of time with a recommended dose of 15 Gy (19). A randomized trial compared endobronchial brachytherapy (15 Gy at 1-cm distance) to external beam RT (30 Gy in 10 fractions) in palliative treatment of patients with NSCLC (20). In 99 previously untreated patients, symptom relief was comparable although fewer retreatments were needed in the external beam RT arm. Survival was also statistically better in patients treated on the external beam RT arm (9.5 vs. 8.3 months).

Conclusion: RT is an extremely effective palliative treatment in advanced lung cancer. It is most appropriately utilized if symptoms are localized and can often achieve urgent palliation of symptoms such as hemoptysis, airway obstruction, or superior vena cava (SVC) syndrome. There is little evidence to support combining chemotherapy and RT in the palliative setting. Therefore, one modality or the other should be utilized at one time to avoid the combined side effects of both modalities.

SVC Syndrome

SVC syndrome is a group of signs and symptoms resulting from compression or occlusion of the SVC. SVC syndrome is the manifestation of impaired return of venous blood from the face, neck, upper extremities, and upper thorax. This impaired venous ^{drainage results in venous hypertension and subsequent venous congestion. Treatment aims to provide relief of symptoms based on the underlying cause (21).}

SVC obstruction may be caused by direct invasion and compression of the SVC by the primary tumor or by nodal compression of the SVC. The distinction is important because resection of the SVC directly invaded by NSCLC can result in cures, whereas resection of the SVC compressed by paratracheal nodal metastases results in no 5-year survivors (22).

The goals of treatment for SVC syndrome are relief of the obstruction and improvement in symptoms. Steroids and diuretics are often given to decrease edema and inflammation. There are no controlled studies that document the efficacy of this intervention, which remains controversial (21). RT will relieve symptoms; however, it may take weeks. About 85% to 90% of patients report symptomatic relief within 3 weeks (23,24). Chemotherapy may be the treatment of choice if the maximum RT dose has been reached or the tumor is very chemosensitive, like lymphoma or small-cell lung cancer (25).

Stenting provides the most rapid resolution of symptoms. Angioplasty may be performed in conjunction with venography and stenting. Preprocedure venography identifies the site of stenosis or occlusion and the presence of any thrombi, while postprocedure venography documents successful deployment and placement of the stent (23,26).

Pain

Pain is very prevalent in many types of advanced cancer, and more than one-third of patients report their pain as moderate to severe. In a meta-analysis of 52 studies, 55% of 1,546 patients with lung cancer reported pain (27). Other than chest wall pain from direct tumor invasion, common pain syndromes in these patients include bone metastases and Pancoast tumors.

Bone Pain

Bone metastases will occur in 30% to 65% of patients with lung cancer (28). Bone metastases occur in various forms that can have a significant impact on the patients’ quality of life. Complications from bone metastases can include pathologic fracture, spinal cord compression, and hypercalcemia. Bone pain often requires multimodality management with opioid narcotics, bone radiation, and possible surgical intervention. Orthopedic surgery consultation should be obtained when there is a bone fracture or an impending fracture of a weight-bearing bone as defined by erosion of 30% or more of cortical thickness as seen on plain radiographs.

Radiation therapy: External beam RT can provide significant palliation of painful bone metastases in 50% to 80% of patients with up to one-third of patients achieving complete pain relief at the treated site (29). There is significant variation worldwide in dose fractionation schedules (30). There have been numerous prospective randomized and retrospective trials that have shown similar pain relief outcomes with single-fraction schedules compared to longer courses of palliative RT for previously unirradiated bone metastases. The greatest advantages of a single-fraction treatment are increased convenience and lower cost.

There is also a wide range of radiotherapeutic options for pain that recurs after standard RT. Painful bone lesions at several anatomic sites can be treated with injectable radiopharmaceutical agents or hemibody RT depending on tumor histology and the distribution of the metastases. There has also been significant interest devoted to technological advances in RT delivery, such as stereotactic body radiation (SBRT), which can improve the results of primary or repeated treatment of metastatic spinal lesions. Although clinical trials with bisphosphonates initially consider the need for external beam RT as a failure of therapy, external beam RT to the index lesion may symptomatically provide more prompt and durable symptom relief (31).

Clinical trials: Many clinical trials have evaluated different dose and fractionation schemes for treatment of painful bone metastases. One of the largest trials was performed in 1999 by the Bone Pain Trial Working Party. This trial enrolled 775 patients with various cancer types, the majority of whom had lung cancer, and randomized them to receive 8 Gy in a single fraction versus 20 Gy in five fractions or 30 Gy in 10 fractions. Overall pain relief was equivalent in both arms at 78% and the complete response rate was also equivalent at 57% in the 8-Gy arm and 58% in the multifractionation arm. In addition, acute toxicity was similar in both arms and late toxicity was minimal. There was a higher retreatment rate in the single-fraction arm with 23% of the patients necessitating repeat treatment compared to 10% of patients in the multifractionation arm (32). Another large trial performed by Steenland et al. included 1,171 patients with various cancer subtypes who were randomized to receive either 8 Gy in a single fraction or 24 Gy in 6 fractions. Overall pain relief was similar in both arms (72% vs. 69%, respectively). Twenty-five percent of patients required retreatment in the single-fraction arm compared to 7% in the multifraction arm (33).

As is seen in Table 16.1, multiple other trials have demonstrated similar rates of complete response to pain with single-fraction treatments compared to multifraction regimens. However, there is also a significantly higher retreatment rate in the single-fraction arms. Care must be taken to appropriately select patients for single-fraction treatments. If survival is thought to be limited, then a single-fraction course might be reasonable. If survival is expected to be relatively long, a multifraction treatment schema might be better suited for the patient. As part of ASTRO’s Choosing Wisely campaign, clinicians are asked to consider a shorter fractionation course for patients with painful bone metastases based on the evidence described earlier (41).

Radiopharmaceutical therapy: Since multiple sites of osseous metastases are common and some patients have multifocal bone pain, systemic-targeted treatment offers the potential for pain relief with minimal side effects. Radiopharmaceuticals developed for the treatment of painful bone metastases include phosphorus 32 (P32), strontium 89, and samarium 153. All of these agents have specific advantages and toxicities, and they differ in terms of mechanism of action, efficacy, duration, palliation, side effects, and the ability to repeat treatment. Phosphorus and strontium distribute more widely throughout the bone.

P32 is a reactor-produced, pure beta-emitting radionucleotide with a physical half-life of 14.3 days. The maximum and mean beta particle energies are 1.71 and 0.695 MeV, respectively, where the mean and maximum particle ranges in tissue are 3 and 8 mm, respectively. P32 was one of the first radiopharmaceuticals used to reduce pain from bone metastases, being widely used until the 1980s (42). Pain palliation typically occurs within 14 days with a range of 2 days to 4 weeks. The major side effects of P32 are myelosuppression and pancytopenia.

Strontium is an element that behaves biologically like calcium. It localizes in bone, primarily in areas of osteoblastic activity. Strontium 89 has a physical half-life of 50.5 days, a maximum beta particle energy of 1.46 MeV, and a soft tissue range of 2.4 mm. After IV administration, strontium 89 is concentrated in bone in proportion to osteoblastic activity with a biological half-life of 4 to 5 days (43). Strontium 89 can relieve bone pain for up to 14 months and is recommended for use in patients with moderate pain with a reasonable life expectancy. Response rates range from 60% to 84% with an onset of pain relief of 7 to 21 days and a mean duration of relief of about 6 months (44). However, a transient increase in bone pain can occur within the first 2 to 3 days of treatment. This flare is usually mild, can be controlled with over the counter analgesics, and usually indicates a good response to treatment.

The final radionucleotide worth mentioning is samarium 153, which has a physical half-life of 1.9 days, a maximum beta particle energy of 0.81 MeV, and an average soft tissue range of 0.6 mm. This agent works by forming a phosphonate complex that concentrates in bones in areas of osteoblastic activity. Approximately 65% of the dose remains in the skeleton. Effective palliation occurs in about 62% to 74% of patients (45–47). Samarium 153 is the most widely used pain palliation radiopharmaceutical agent in the United States. Its ease of use, the ability to image its distribution, and its clinical results make it attractive, while issues with availability, radiation safety, and potentially irreversible myelosuppression limit wider use.

Medical Management of Bone Pain

The primary treatment for the source of bony pain is RT. However, other measures should be taken for pain relief while waiting for the treatment to take effect, which could be days to weeks.

Nonsteroidal anti-inflammatory drugs (NSAIDs): NSAIDs block biosynthesis of prostaglandins, the inflammatory mediators that cause and intensify pain. NSAIDs are a mainstay in the treatment of bony metastases, although all patients (and elderly patients in particular) should be watched closely for gastric irritation and renal insufficiency.

Bisphosphonates and RANKL inhibitors: Bisphosphonates, such as zoledronic acid and ibandronate, and RANKL inhibitors, such as denosumab, have demonstrated effectiveness in preventing skeletal related events and have been shown to palliate existing bone pain. In a randomized trial comparing denosumab to zoledronic acid in breast cancer patients with bony metastases, 26% of patients in both arms experienced meaningful pain relief. Fewer patients receiving denosumab complained of worsening of pain and there was also a longer time to worsening of pain in the denosumab group (48).

Opiates: Opiates are useful for most types of moderate to severe pain, although bony pain usually requires the addition of other adjuvant analgesics, such as an NSAID. When opiates are used, the basic principles of opiate therapy should be followed:

•    The lowest effective dose should be used, to minimize the risk of side effects. Typically, an opiate-naïve patient should be started on a mild opiate, such as hydrocodone or codeine on an as-needed basis (49).

•    If pain is chronic and requires numerous doses of immediate-release medication, then an extended-release opiate should be added. This can be started at the lowest dose available, or if information is available from the patient’s use of opiates for breakthrough pain, then the extended-release dose should reflect the total amount that the patient has been taking in an average 24-hour period.

•    Opiate toxicities should be carefully monitored. Constipation is the most common side effect, so a laxative should be routinely prescribed when an opiate is started. Nausea and sedation are other possible negative effects, but they may subside over a period of days.

Chest Wall Pain and Pancoast Tumors

Pancoast tumors involve the superior pulmonary sulcus and were described by Henry Pancoast in the early 1900s. Typically pain is experienced in the shoulder and arm, in the distribution of the C8, T1, and T2 dermatomes, and can be associated with muscle weakness and atrophy. The tumor can invade the brachial plexus, and therefore pain is often neuropathic in nature. Patients may experience prickling, burning, and numbness. Medications that may be helpful to relieve the neuropathic aspect of the pain include antidepressants and anticonvulsants (50). Much of the data supporting these agents are extrapolated from nonmalignant neuropathic pain management studies, such as those for diabetic neuropathy. These adjuvant agents are frequently used in combination with opiates for moderate to severe neuropathic pain.

In situations where the tumor is unresectable and palliative RT is either not feasible or ineffective, some pain relief interventions have been used successfully. These include continuous interscalene brachial plexus block via catheter, selective cervical nerve root blocks, dorsal rhizotomy, and cordotomy. The best treatment depends on the size of the tumor, the extent of local invasion, and the specific structures involved. An intercostal nerve block can be very useful for localized chest wall pain. If the pain remains difficult to control despite the best efforts at medical management, then the Anesthesia Pain Service should be consulted for their input.

Tricyclic antidepressants and serotonin–norepinephrine reuptake inhibitors (SNRIs)

•    Start with a low dose to make sure that the medication is tolerated; then titrate upward every 3 to 5 days, as tolerated.

•    The dose needed for pain control may be lower than doses typically used for treatment of depression.

•    Tricyclic antidepressants: Anticholinergic side effects include dry mouth, sedation, and urinary hesitancy. Secondary amines such as nortriptyline or desipramine have less of these effects and are most commonly used.

•    SNRIs: Duloxetine and venlafaxine are most commonly used. In a randomized cross-over trial with 231 patients with chemotherapy-induced neuropathy, duloxetine improved the Brief Pain Inventory score and quality of life as measured by Functional Assessment of Cancer Therapy (FACT)-Neurotoxicity assessment (51).

Anticonvulsants

•    Start low and titrate up as tolerated. The patient may get relief from neuropathic pain at relatively low doses.

•    Gabapentin: The starting dose is 100-mg TID, but there is a large dosing range and doses may be titrated up to 1,200-mg TID as needed. Sedation can be a dose-limiting toxicity.

•    Pregabalin: The starting dose is 50-mg TID and may be doubled over time. Fluid retention and peripheral edema may occur.

Fatigue

Cancer-related fatigue is the most common and distressing symptom affecting patients who are undergoing chemotherapy and/or RT, or who have metastatic disease. Fatigue can disrupt functionality and affect activities of daily living for months after treatment, and for some patients indefinitely (52). Physicians should screen patients for fatigue at each visit or this symptom may get lost in the assessment for more “pressing” problems, such as pain or nausea/vomiting.

Correctable factors that may contribute to fatigue and their primary treatments include:

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